Vitexin Mitigates Myocardial Ischemia/Reperfusion Injury in Rats by Regulating Mitochondrial Dysfunction via Epac1-Rap1 Signaling.

Huanhua Yang,Binshan Zha,Wei Xue,Caijuan Ding,Liuyi Dong,Yuqian Sun,Junyan Zhang,Huaqin Zhu,Cheng Wang,Shuo Chen,Bohan Xu,Vladimir Jakovljevic

doi:10.1155/2021/9921982

Abstract

Revascularization is an effective therapy for rescuing myocardial tissue after ischemic events. However, the process of reperfusion can lead to more severe cardiomyocyte damage, called myocardial ischemia-reperfusion (I/R) injury (MIRI). We have previously shown that vitexin (VT) (a flavonoid compound derived from natural products) protects against MIRI; however, the exact mechanisms underpinning this effect require further elucidation. This study is aimed at elucidating the protective mechanism of VT in inhibiting ischemic myocardial mitochondrial dysfunction and reducing cardiomyocyte apoptosis by regulating Epac1-Rap1 signaling. Isolated rat hearts were subjected to MIRI in a Langendorff perfusion system, and H9c2 cells were subjected to hypoxia/reoxygenation (H/R) in vitro. Our analyses show that during I/R, Epac1 expression was upregulated, left ventricular dysfunction deteriorated, mitochondrial dynamics were disrupted, and both myocardial cells and tissues exhibited apoptosis. Furthermore, administration of 8-CPT (an Epac agonist) exacerbated cardiomyocyte injury and mitochondrial dysfunction. Interestingly, suppressing the function of Epac1 through VT or ESI-09 (an Epac inhibitor) treatment during I/R reduced the myocardial infarct size, cardiomyocyte apoptosis, and reactive oxygen species production; alleviated mitochondrial dysfunction by increasing mitochondrial membrane potential; elevated MFN2 expression; and inhibited Drp1 expression. To our knowledge, our results reveal, for the first time, the mechanisms underlying the protective effect of VT in the myocardium of rats with MIRI. Moreover, we provide a new target and theoretical basis for VT in the treatment of ischemic heart disease.

Highlights

Ischemic heart disease has long been one of the leading causes of death worldwide, with high morbidity and mortality [1]
Our results showed that there was no significant difference in the baseline values of cardiac function parameters between the groups during the perfusion equilibrium phase
At the end of reperfusion, coronary flow (CF) (Figure 1(a)), heart rate (HR) (Figure 1(b)), left ventricular systolic pressure (LVSP) (Figure 1(d)), and ± dP/dtmax (Figures 1(e) and 1(f)) considerably reduced, whereas Left ventricular end-diastolic pressure (LVEDP) significantly increased in the I/R group compared to that in the control group (Figure 1(c))

Summary

Introduction

Ischemic heart disease has long been one of the leading causes of death worldwide, with high morbidity and mortality [1]. Revascularization is the most effective therapy for rescuing ischemic cardiomyocytes, and it can significantly reduce complications and mortality. Coronary artery occlusion and abrupt recovery of blood flow can lead to more severe cardiomyocyte damage, which is called myocardial ischemia-reperfusion (I/R) injury (MIRI) [2]. Cardiac dysfunction caused by MIRI includes several types of fatal reperfusion injury, no-reflow phenomenon, and perfusion arrhythmia [3, 4]. Drug intervention has been considered relatively beneficial for the treatment of cardiac ischemia [8], and the cardioprotective effects of drugs are attracting increasing attention from researchers [9]

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